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TREATMENT OF TOURETTE’S
5. Use of stimulants. Because stimulants can make
tics worse, it is often assumed that stimulants are con-
SYNDROME
traindicated in the treatment of TS. In reality, the ticsare often mild and easy to treat, and it is the co-morbid
ADHD that causes the greatest disability. Failure
to address and treat the ADHD can leave a patient
significantly disabled. TS and ADHD are intimately
related clinically, genetically, and pharmacologically.
6. Exacerbation of tics by medications. Although it is
Tourette’s syndrome (TS) is a complex neurobehav-
well known that stimulants can exacerbate tics in
ioral disorder. Its diagnosis is based on the occurrence
individuals with TS, it is less well appreciated that
of motor and vocal tics almost daily for a period of at
virtually every medication used in the treatment of
least 1 year. Coprolalia is seen in less than 10% of
TS and its co-morbid conditions can, in some cases,
patients and is not required for the diagnosis. TS is a
make the tics worse. Such medications include cloni-
strongly genetic disorder. Like other behavioral condi-
dine (Catapres), clonazepam (Klonopin), haloperidol
tions, TS is a polygenic disorder caused by the additive
(Haldol), pimozide (Orap), and risperidone (Risperdal).
and epistatic effect of multiple genes interacting with
7. Polypharmacy. The use of multiple medications
the environment, each with a small effect. TS should
used to be considered bad medical practice. However,
be considered a disorder with a wide spectrum of
behavioral disorders are due to the combined effect
manifestations. Thus, the feature that makes it so
of multiple different gene variants, each affecting
intriguing is the wide range of co-morbid disorders
different neurotransmitters and other pathways and
that occur in over 80% of individuals who seek medical
each of which may require a different medication for
attention. These disorders include attention deficit
hyperactivity disorder (ADHD), learning disorder,
8. Drug of choice. Clonidine,* not haloperidol or
obsessive-compulsive disorder (OCD) or behavior,
pimozide, is the drug of first choice.
other anxiety disorders including panic attacks and
Medications for the treatment of tics can be divided
generalized anxiety disorder, mood disorders including
into two groups. Group I consists of those that are effec-
depression and mania, sleep disorders, oppositional
tive 60% to 80% of the time, and group II includes drugs
defiant disorder (ODD) and conduct disorder, rages,
that are less consistently effective or often ineffective.
self-destructive behavior, and others. Space does notallow a discussion of the treatment of these co-morbiddisorders. The focus here is on the treatment of tics.GROUP I MEDICATIONS
This article is based on my personal experience
In my experience, only three medications or groups
over the past 25 years with the treatment of over 4000
of medication are included in group I. In order of
children and adults with TS. The following are some of
preference, they are clonidine,* clonazepam,* and the
what I consider basic truths concerning the treatment
typical or atypical neuroleptics (Table 1). In the fol-
lowing sections, the generic names are given first and
1. Treatment of the whole person. Anyone who takes
the U.S. brand names are given in parentheses. They
on the treatment of individuals with TS should be
are often different in other countries.
prepared to treat the whole spectrum of co-morbiddisorders because of the intimate interaction between
Clonidine (Catapres)
the tics and the co-morbid behavior. Moreover, itusually works best for the patient and the physician
Clonidine* is an α -adrenergic agonist. By stimulat-
if one person treats both disorders.
ing presynaptic α -adrenergic receptors, in modest
2. Waxing and waning of tics. The spontaneous
doses it results in a decrease in norepinephrine (NE)
waxing and waning of motor and vocal tics can make
release. At higher doses it can stimulate postsynaptic
evaluation of the true effectiveness of medications
α-adrenergic receptors. Clonidine is effective in the
difficult. This difficulty increases the need to use
treatment of motor and vocal tics 60% to 70% of the
double-blind assessments when evaluating the efficacy
time. However, it is a short-acting medication, and
when given orally, the effects can wear off after 3 to
3. Tics may be the least of the problems. In most
6 hours. Clonidine is also effective in the treatment
cases, the tics are often the easiest part of the spectrum
of ADHD, and considerable evidence indicates that
to treat and are the least of the problems. Once the tics
NE plays a significant role in ADHD. Importantly,
are minimized with medication, it is often the ADHD,
elevated plasma levels of NE breakdown products
OCD, or ODD that is the major issue in treatment.
have been associated with learning disorders in indi-
4. Basic pharmacology. Many times the difference
viduals with ADHD, which suggests that reducing NE
between success or failure in the treatment of TS
levels could benefit children with learning disorders.
lies less in finding exotic new treatments for difficult
Finally, clonidine* can be effective in the treatment of
cases and more in understanding the best route and
ODD, OCD, anxiety, phobias, and panic attacks. Thus,
timing of administration of a small number of themost effective and reliable medications.
*Not FDA approved for this indication.Rakel and Bope: Conn’s Current Therapy 2004. Copyright 2004 by Elsevier Inc.
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TREATMENT OF TOURETTE’S SYNDROME
TABLE 1. Primary Groups of Drugs for the Treatment of Chronic Tics in Tourette’s SyndromeAverage Dose
*Not FDA approved for this indication†Not available in the United States.
clonidine can be effective in the treatment of many of
The most common errors leading to treatment fail-
the important co-morbid conditions. It is especially
ure in treating TS subjects with the clonidine patch*
relevant that clonidine is one of the very few medica-
are starting with a whole patch then abandoning
tions that can consistently and reliably treat both tics
treatment because of too much sedation or because it
and ADHD. This property makes it a particularly
was ineffective. The problem with sedation can be
valuable alternative to the use of stimulants in the
avoided by cutting the patch and starting with less
treatment of TS subjects with co-morbid ADHD.
than a whole patch. The medication does not leak out
Because it is effective for such a broad range of the TS
of a cut patch. I have seen many cases in which a
spectrum, I start treatment of most TS patients and
whole patch was too much, 1/2 patch was too little, but
many mild to moderately severe ADHD patients with
3/4 or 7/8 of a patch was just right. The problem with a
clonidine. It covers a range of symptoms, so successful
whole patch being ineffective can often be avoided
initiation of treatment with clonidine can often obvi-
by further increasing the dose. The maximal dose is
ate the need to use any other medication. A number
two TTS-3 patches. The average dose is one to two
of strategies can be used to maximize the advantages
patches. It is common for the patch to be effective for
of clonidine and minimize the disadvantages. With
several weeks and then lose its effectiveness. This
the use of these strategies, a sizable number of TS
change in effectiveness can usually be eliminated by a
patients can be effectively treated with clonidine
further increase in the dose. Only one to two such
alone. If additional medications are needed, the dose
upward adjustments are typically required. Parents
required is often less than if a foundation of clonidine
and patients seem to understand these changes
best when told that “the dose is adjusted with a pair of
Transdermal Clonidine (Catapres-TTS). The
scissors.” It is also important to let them know that
single major disadvantage of clonidine* is that it can
they do not need to call the doctor with every change
be very sedating, especially when given orally.
in dose. They can be given a range to operate within,
However, this side effect and the need to give frequent
doses because of its short duration of action can be
One of the most common problems with use of the
ameliorated by the use of transdermal clonidine,
clonidine patch* is the development of a rash immedi-
known as the Catapres Transdermal Treatment
ately under the patch as a result of contact dermatitis.
System.* It is available as TTS-1, TTS-2, and TTS-3.
This rash is due to an allergy to the patch material
The latter two are equivalent to a patch two and three
itself, not the clonidine.* It can often lead to the child
times the size of TTS-1. The use of a TTS-1 patch once
complaining that the patch itches, and the patch will
a week is equivalent to the use of 0.1 mg of oral cloni-
then be pulled off. A first line of defense against such
dine* per day. For children, 1/4 to 1/2 patch per week is
removal is to use only the clonidine patch itself and
the usual starting dose. When the dose is right, the
not the large covering patch that comes in the box.
tics may subside within a few days. If the parents are
In some cases, the allergy is to the covering patch
in a hurry to get the tics under control, the dose can
rather than the clonidine patch itself. A second
be increased every 1 to 2 days. If they are not so des-
approach is to change the patch every 3 to 4 days
perate, the dose is usually increased by 1/2 patch every
instead of weekly. Because the rash sometimes occurs
week until satisfactory control of the tics or too much
predominantly on days 5 to 7, earlier changing can
sedation is noted. In most cases, 1/2 patch has no effect,
avoid the problem. Another approach is to have
and it is thus necessary to increase to a whole patch.
the patient or parents purchase some water-based,
*Not FDA approved for this indication.
*Not FDA approved for this indication.Rakel and Bope: Conn’s Current Therapy 2004. Copyright 2004 by Elsevier Inc.
Rakel & Bope_Section-14 10/29/03 12:55 PM Page 961
TREATMENT OF TOURETTE’S SYNDROME
over-the-counter hydrocortisone ointment and rub it
every 3 to 6 hours. Parents often report that they can
into the area where the patch is to be placed, let it dry,
see the medication wearing off after this time interval.
and then apply the patch. If all these measures fail,
They can repeat the dose as often as necessary by
and they do about 20% to 30% of the time, a final very
using a dose just under that causing tiredness. Many
effective approach is to switch to clonidine cream.*
patients report that their physicians have previously
The patch also becomes very difficult to use in the
treated their TS with oral clonidine but suggested
summer when children sweat a lot or swim. Although
they take it at bedtime to avoid problems with seda-
the patch is waterproof and can resist brief showers,
tion. Although such administration can be effective
tub baths, and brief dips in the pool, it is not compat-
because of the short duration of action of clonidine, it
ible with daily swims of an hour or more. These situa-
often results in less than optional control of the tics in
tions also call for the use of clonidine cream** or an
oral form of clonidine or guanfacine (Tenex).†
Clonidine as a Sleeping Medication. In manyClonidine Cream.∗∗ I have had hundreds of TS
cases, what is usually considered an undesirable side
patients who responded to only clonidine patches†
effect can become an effective therapeutic effect.
and in whom no other medications were effective,
Because NE is the arousal neurotransmitter, individ-
including oral clonidine,† haloperidol, and pimozide.
uals with elevated central nervous system NE are
When only patches are effective and then a severe
often overaroused, especially children with TS and
allergic reaction develops to the patch such that it can
ADHD. Clonidine* can be a very effective, non–habit-
no longer be used, patients or parents are devastated.
forming, nonaddictive sleeping aid for such individ-
In the past 5 years I have found that an excellent
uals. The bedtime dose usually ranges from 0.1 to
solution to this problem is to switch to clonidine
0.3 mg. Occasionally, parents complain that their
cream. It is not available at most pharmacies, but
TS/ADHD children wake up and roam the house in the
fortunately, usually at least one pharmacy in each
middle of the night. Because of its short duration of
reasonably large city does compounding and can
action, clonidine is excellent for inducing sleep but is
make clonidine in cream form. If the patient had been
less effective in maintaining sleep throughout the
using a TTS-1 patch, the prescription would read
night. A clonidine patch* can be helpful in this regard.
0.1 mg/0.1 mL, use 0.05 to 0.15 mL on the forearm
The combination of a clonidine patch* supplemented
one to two times daily, with the amount being
with bedtime oral clonidine* can treat both problems
“1 month’s supply.” The cream is supplied in tuberculin
of getting to sleep and staying asleep.
syringes with a plastic cap. The markings allow easy
Although both clonidine* and guanfacine* are blood
dispensing of 0.1 mL. The patient, not the parent,
pressure medications, hypotension is rarely a trouble-
should rub it into the forearm and make sure that no
some side effect. Even fairly substantial doses are
clothing comes in contact with it for 30 minutes. By
not associated with significant decreases in blood
this time the medication has been adsorbed into the
pressure, thus suggesting that in the absence of
skin and will not rub off. It will also not sweat off and
hypertension, only a modest decrease in blood
will not come off in the pool. In those who swim a lot,
pressure occurs. In addition, these medications have
an alternative is to use the cream after swimming
no significant effect on the QT interval.
each day. In some cases, morning and afternoon
Much time was devoted to the use of clonidine*
application of the cream is necessary to keep symp-
because it can be so effective in the treatment of TS
toms in check. If a compounding pharmacy is not
and its co-morbid conditions. In some children with
located in your area, one might be found on the
significant motor and vocal tics, ADHD, learning prob-
Internet. Many compounding pharmacies will fill pre-
lems, OCD, and ODD who are failing all their classes
scriptions from any state or country.
and are a constant visitor to the principal’s office
Oral Clonidine. Oral clonidine** is the last prefer-
because of disruptive behavior, all these symptoms
ence for a route of administration of clonidine.** In
have disappeared after the use of a clonidine patch.*
my experience, oral clonidine is much more likely to
Equally impressive, after several months their grades
cause an unacceptable degree of sedation than trans-
may have risen to A’s and B’s. Some children have
dermal clonidine** is, probably because of the fact
returned to the clinic proudly displaying plaques for
that blood levels rise quickly after oral administration
“most improved student.” Not all children responded
and result in a higher blood level than what is
obtained with transdermal clonidine.** Blood levelsthen drop and the tics return. Thus, as the parents
Guanfacine (Tenex)
or patients recall the day, they are either “tired orticcing.” The even blood levels obtained with trans-
Guanfacine* is also an α -adrenergic agonist. It has
dermal clonidine** avoid this up-and-down course.
a slightly longer duration of action than oral cloni-
Nonetheless, some patients still prefer oral clonidine.
dine* does and a modestly lower incidence of sedation
The side effects can be minimized by giving the med-
as a side effect. As such, it is widely used in place
ication in small, frequent doses such as 0.025 or 0.05 mg
of oral clonidine. The usual starting dose is 0.25 to0.5 mg three times daily (tid). Maintenance dosesare usually 0.5 to 1 mg tid. Guanfacine has all the
*May be compounded by pharmacists.**Not commercially available in the United States.†Not FDA approved for this indication.
*Not FDA approved for this indication.Rakel and Bope: Conn’s Current Therapy 2004. Copyright 2004 by Elsevier Inc.
Rakel & Bope_Section-14 10/29/03 12:55 PM Page 962
TREATMENT OF TOURETTE’S SYNDROME
advantages of clonidine. However, as with oral cloni-
Atypical Neuroleptics
dine, it can still be unacceptably sedating, and I preferthe clonidine patch* to both oral clonidine and oral
Atypical neuroleptics have the advantage that they
are much less likely to cause tardive dyskinesia,
One of the side effects of both clonidine (in any
predominantly because of the fact that they cause
form) and guanfacine is that instead of decreasing
less inhibition of dopamine D receptors. However,
symptoms of overarousal and hyperactivity, it can
inhibition of these receptors is the reason that neu-
increase these symptoms. Thus, in about 5% to 10% of
roleptics are so effective in the treatment of tics. Of
cases, parents report that their children are more
the atypical neuroleptics (risperidone [Risperdal],*
active and more irritable and have more trouble sleep-
olanzapine [Zyprexa],* molindone [Moban],* ziprasi-
ing. It has been suggested that ADHD is primarily a
done [Geodon], quetiapine [Seroquel],* clozapine
disorder of NE regulation and that both too little and
[Clozaril]), risperidone* has the greatest affinity for
too much NE can cause problems of inattention. Thus,
dopamine D receptors. This affinity conforms with
if a child had a low-NE form of ADHD, clonidine*
my clinical experience that it is also the most effective
could make it worse. Alternatively, as mentioned ear-
atypical neuroleptic for the treatment of tics. Starting
lier, at higher doses clonidine can have direct action
doses are usually 0.25 to 0.5 mg tid, with maintenance
on postsynaptic α-adrenergic receptors. This effect
doses of 0.5 to 1 mg tid. Risperidone is relatively short
could also result in activation rather than suppression
acting. A common reason for failure of risperidone
is administration of the medication only one or twotimes per day. If these times are in the morning andevening, recurrence of tics in the afternoon or evening
Clonazepam (Klonopin)
may seem to be a failure of the drug. This “failure”
Clonazepam* is one of the most frequently over-
can often be eliminated by giving a third dose at
looked medications for the treatment of tics. When
clonidine* is less than optimally effective, clonazepammay be the second drug of choice. The starting dose is
0.125 to 0.25 mg one to three times per day, dependingon the age of the child. A common maintenance dose is
Group II medications are those that in my experi-
0.25 to 0.5 mg tid. As with clonidine, the major side
ence are effective in less than 50% of cases, are not
effect is sedation. Other benzodiazepines may also be
generally available in the United States, or require
effective. Although the dependency potential of clon-
special expertise. Careful attention to the use of type I
azepam is often a concern, it is very rare for TS individ-
medications results in control of tics in over 90% of
uals to request progressively higher and higher doses.
TS cases. Group II medications and treatments, inalphabetical order, include antiandrogens, antibiotictreatment of PANDAS (pediatric autoimmune neu-
Neuroleptics
ropsychiatric disorder associated with streptococcal
Neuroleptics such as haloperidol (Haldol), pimozide
infections), anticonvulsants, baclofen (Lioresal),
(Orap), and fluphenazine (Prolixin)* used to be the
behavioral management, β-blockers, botulinum toxin,
drugs of choice for treating TS. They are effective in
calcium channel blockers, clomiphene citrate
80% of cases. However, with the advent of the Web,
(Clomid), cyproterone (Androcur),† deprenyl (Eldepryl),*
parents often check out medications before using
dronabinol (Marinol), electroencephalographic biofeed-
them, and the statement that permanent neurologic
back, herbal remedies, 5-hydroxytryptophan,† lecithin,
changes such as tardive dyskinesia can occur often
marijuana, mecamylamine (Inversine),* metoclo-
frightens parents and patients so much that these
pramide (Reglan),* naltrexone (ReVia),* nicotine patch
neuroleptics have de facto become drugs of third
(Habitrol),* ondansetron (Zofran),* pergolide (Permax),
choice. If clonidine* and clonazepam* have been inef-
reserpine, selective serotonin reuptake inhibitors,
fective, before neuroleptics can be used, it is often nec-
tetrabenazine,‡ tramadol (Ultram), tricyclic antide-
essary to calm parents’ fears of them. I have treated
pressants, and L-tryptophan. Interested readers can
over 2000 TS patients with a major neuroleptic and
obtain further details from the National Library of
have seen only 2 cases of mild tardive dyskinesia, both
in individuals who received over 15 mg/d of haloperi-
In the vast majority of cases, the motor and vocal
dol for many years. The usual doses of these medica-
tics of TS or the chronic motor tic disorders can be
tions are 0.25 to 2 mg of haloperidol, 0.5 to 4 mg of
effectively treated with the use of one or more of the
pimozide, and 0.5 to 5 mg of fluphenazine per day.
type I medications listed earlier. The difference
Although at these low doses occasional patients may
between success and failure often lies less in turning
have akathisia, or extrapyramidal symptoms, I have
to type II medications and more in paying careful
never seen a case of tardive dyskinesia. Patients
attention to the pharmacologic aspects of the three
should have the QT interval monitored when taking
*Not FDA approved for this indication.†Investigational drug in the United States.‡Not available in the United States.
*Not FDA approved for this indication.Rakel and Bope: Conn’s Current Therapy 2004. Copyright 2004 by Elsevier Inc.